key: cord-0957700-08ics9u1 authors: Valentino, Leonard A.; Oza, Veeral M. title: Blood safety and the choice of anti‐hemophilic factor concentrate date: 2006-05-24 journal: Pediatr Blood Cancer DOI: 10.1002/pbc.20895 sha: 2eb92da0eb2bc75d6d1ab406d2a944b231570e72 doc_id: 957700 cord_uid: 08ics9u1 Hemophilia is a congenital disorder due to the deficiency of the activity of factor VIII (classical hemophilia A) or IX (Christmas disease or hemophilia B). Bleeding is common and may result in long‐term complications or even death. Bleeding may be treated or prevented by infusion of factor concentrates however these drugs are not without risk. Clinicians often feel ill prepared to provide accurate and impartial information regarding these drugs. This review will provide the reader with an historical yet up to date perspective on blood safety as it relates to the choice of concentrates to treat hemophilia. Pediatr Blood Cancer 2006;47:245–254. © 2006 Wiley‐Liss, Inc. Hemophilia is a genetic disorder that is due to the deficiency or absence of a protein necessary for normal blood clotting. Treatment consists of regular injections of antihemophilic factor concentrates given on an ''as needed basis'' (episode-based treatment) or according to a regular schedule of prophylactic infusions (prophylaxis) to prevent bleeding and the debilitating complications that ensue from bleeding into joints, muscles, or vital organs and structures. The National Hemophilia Foundation's MASAC [1] and the Canadian Hemophilia Treatment Center Directors [2] both advise that physicians exercise their best judgment in advising patients about their options in terms of product for treatment of bleeding episodes. The choice of which factor concentrate to use is a difficult decision for parents of young children, adult patients, and their physicians. Factors that impact on this decision (Table I) include availability of individual products, their cost, clinical effectiveness, ''ease of administration,'' and the safety of each product [3] . In 2000, more than three billion international units of recombinant anti-hemophilic factor concentrate were produced [4] . This amount is capable of meeting the needs of only 30% of the world hemophilia population. The issues of cost and cost-benefit of individual anti-hemophilic factor concentrates are beyond the scope of this review. The reader is referred to an excellent review by Giagrande [5] on this topic. Similarly, data on the effectiveness of individual antihemophilic factor concentrates is present in the literature [6, 7] . Prospective trials, retrospective analyses and case reports examining the effectiveness of individual products can be found in the literature and will not be discussed here. The safety of anti-hemophilic factor concentrates is a major concern for patients with hemophilia and parents of young children with hemophilia [8] [9] [10] . Any discussion of product safety should include consideration that the product could potentially transmit a serious, life-threatening infection, induce the formation of a neo-antigen or inhibitor, or cause allergic or other adverse effects [3, 11] . Physicians treating hemophilia patients often lack answers to the same questions that patients or their parents have. The discussion here will focus on blood safety as it relates to the choice of a factor concentrate to treat patients with hemophilia. To illustrate key points in the decision making process, three clinical scenarios will be presented. Each case illustrates different issues facing the clinician providing care for patients with hemophilia. Case 1 (Viral infection) is that of a 34-year-old male with severe hemophilia A and chronic degenerative joint disease involving both ankles and elbows and his right knee. The patient receives episodic infusions of 2000 International Units (IU) of factor VIII concentrate as needed. Annually, he infuses approximately 160,000 IU. Over his lifetime he has received more than 2,000 infusions without the development of an inhibitor, an antibody that precludes the function of the infused factor concentrate. During early adolescence, he was treated with a factor concentrate that was contaminated with the virus that causes AIDS-human immunodeficiency virus 1 (HIV-1). Despite almost 20 years of infection, his viral load is minimal (less than 100 viral genome copies per ml) and his CD4 T-lymphocyte cell counts are moderately reduced despite not ever receiving anti-retroviral therapy. He was also infected with hepatitis C virus (HCV) from contaminated factor concentrate and currently has evidence of moderately severe liver dysfunction with prolongation in the Prothrombin time and elevated liver transaminases, for which no therapy has been given. Case 2 (Prophylaxis) is that of a 9-year-old boy who has severe hemophilia A. He has had 12 acute hemarthroses affecting the right knee, both ankles and both elbows but none is a target joint. Since 2 years of age, he has been treated with regular prophylactic infusions of factor VIII concentrate three times weekly utilizing approximately 160,000 IU yearly. There has been neither clinical nor laboratory evidence to suggest the presence of an inhibitor. He received vaccines against hepatitis A and B virus infections and has protective adaptive immunity against these viruses. He has not been exposed to hepatitis C or HIV-1 viruses. Case 3 (previously untreated patient) is that of 1½ year old previously untreated boy with severe hemophilia A who presents with his first significant bleeding episode characterized by a warm, tender, swollen right knee. This boy is immune to hepatitis B following vaccination but is at risk for hepatitis A, having not yet initiated the vaccination series, and is at risk for HCV infection as well as for HIV-1 and for other microbes that might be transmitted in antihemophilic factor concentrates. These three cases illustrate some of the issues that patients, parents and physicians face when choosing a factor concentrate for the treatment of hemophilia. Over the past century since first successfully performed in 1818 by James Blundell, a British Obstetrician, transfusion therapy has improved in terms of safety and efficacy. Advances to prevent transmission of microorganisms include donor screening and testing and methods to remove and inactivate microorganisms. Although each of these steps has lead to an improvement in the safety profile of the blood components available to treat patients with hemophilia, the safety of plasma-derived antihemophilic factor concentrates remains an issue. It is more than 30 years since the first cases of infection with hepatitis B virus (HBV) were reported in patients with hemophilia treated with concentrates made from plasma [12] . From 1971 From to 1975 From and 1975 From to 1979 , the annual incidence of HBV infection was estimated to be 7% and 9.5% [13] . Currently, 90% of HBV seroconversions in patients with hemophilia are attributed to vaccination programs [14] . According to the most recent data from the Centers for Disease Control and Prevention, the prevalence of natural or acquired immunity to HBV among the 15,682 people with bleeding disorders participating in the Universal Data Collection (UDC) project [15] appears to be decreasing despite the availability and widespread usage of hepatitis B vaccine in childhood. This suggests that patients may once again be susceptible to HBV infection. The signs and symptoms of hepatitis following infection with HBV are present in about 70% of cases, of which about 5% develop chronic infection and 15%-25% of these individuals die from chronic liver disease [16] . Infection with HCV (formerly called non-A, non-B (NANB) Hepatitis) was described phenotypically as being distinct from Hepatitis A and B in the 1970's and the virus was isolated and genome sequenced in 1989. The prevalence of HCV infection among persons with hemophilia is approximately 60% [17] . Data from the UDC report [15] indicates that the prevalence of HCV infection is about 40%, but among 41-60 year old people with hemophilia is approximately 80%. The higher infection rates in adults reflect exposure to the disease prior to viral inactivation of factor products. HCV infection is the leading indication for liver transplantation. Up to 80% of persons infected with HCV have no signs or symptoms. Chronic infection and liver disease develops in 55%-85% and 70%, respectively and 1%-5% die from chronic liver disease [16] . In 1982-1983, the first cases of hemophilia patients with an unusual immunodeficiency syndrome appeared which were eventually shown to be due to infection with HTLV-III, later renamed human immunodeficiency virus (HIV) [18] . Approximately one-third of people with hemophilia between the ages of 21 and 60 years are HIV-infected [15] . Recently, the possibility of other 'emerging' infections has gained the attention of parents, patients, and providers. In the next section these concerns will be addressed. As the new millennium came, so did new and improved anti-hemophilic factor concentrates. The current generation of plasma-derived and recombinant anti-hemophilic factor concentrates are purer than their predecessors [19] . A question that we must answer however ''Does the enhanced purity of the anti-hemophilic factor concentrate translate to enhanced safety?'' To explore this issue, the risks from plasma-derived and recombinant coagulation proteins must be considered by four distinct time eras. The first era was prior to 1970 when plasma and cryoprecipitate were used to treat patients with hemophilia. The second era was during the 1970's and 1980's when low and intermediate purity products derived from human blood were used to control acute bleeding and prevent bleeding with surgery. The third era began in the late 1980's and extends to current time with the use of high purity, monoclonal anti-hemophilic factor concentrate and recombinant products. The fourth era began in 2000 with the licensure of the current sucrose-formulated products [9, 14, [20] [21] [22] [23] . Each era was marked by the development of purer anti-hemophilic factor concentrates. The microbiological threats or risks to the three patients described above include: bacteria, protozoa, viruses, and prions. Prior to choosing an anti-hemophilic factor concentrate, several questions should be considered. First, ''Is it possible that one of these agents might be present in blood or a blood product?'' Second, ''If a microbe is present in blood or a blood product, is it capable of infecting me or my child?'' Third, ''Is the infectious agent likely to cause significant human disease?'' Finally, ''If present, is the infectious agent removed by currently employed procedures?'' After considering the answers to these questions (Tables II and III) , a patient or parent will be better able to make an informed choice regarding the use of an anti-hemophilic factor concentrate for themselves or their child. Modern blood banking technology and plasma fractionation procedures have essentially eliminated bacteria and protozoan agents from anti-hemophilic factor concentrates [20, [24] [25] [26] [27] . The major pathogens including HBV, HCV, and HIV have been virtually eliminated from the blood supply [28, 29] , leaving other viruses including hepatitis A, parvovirus B19 and the ''so-called'' emerging agents [30] including prions as the main potential threats to the patients who use blood and blood derivatives [14, 23, 31] . Vaccination programs directed against HAV [32] and HBV [33, 34] result in persistent immunity and recent advances suggest that a vaccine against hepatitis C may be forthcoming [35] . The key properties of the common blood-borne viruses (Table III) include resistance to solvent-detergent and heat inactivation and are important determinants of the likelihood of the presence of each agent in blood and blood derivatives. Sentinel virus is a term that is applied to both HAV and parvovirus B 19, because these viruses may reflect the behavior of other potential, unknown pathogens that could be present in the blood supply. HAV is a solvent-detergent resistant RNA virus, and parvovirus B 19 is a DNA virus that is heat resistant. The current viral inactivation techniques are not very effective against these agents and filtration techniques are used to remove these infectious microorganisms. HAV and parvovirus B 19 are potentially very difficult to eliminate from factor concentrates once present in source plasma [36] . Therefore, donor screening to eliminate HAV and PB19 from source plasma is critical [36] [37] [38] . Recent vaccine development studies for PB19 have yielded promising results [39] [40] [41] . In 2004, Ito and coworkers successfully treated a patient with a persistent PB19 infection with a mixture of cyclosporine A and high-dose gamma-immunoglobulin [42] . The reader is referred to an excellent review on the subject by Heegard and Brown [43] . First-generation recombinant human factor VIII concentrates, stabilized with human-plasma-derived albumin before lyophilization are widely used by hemophilia patients, primarily because of the perceived safety in regards to viral infection. However, Schneider et al., and coworkers found that PB19 was frequently present in recombinant coagulation factor VIII products [44] . Moreover, another study indicated the presence of PB19 in young patients with hemophilia A [45] . Similarly, circoviruses are also very resistant to treatment with heat, detergents, and disinfectants. Recent studies have linked novel circoviruses to serious posttransfusion conditions. For example, transfusion transmitted virus (TTV) was discovered in 1998 [46] and linked to post-transfusion hepatitis [46] [47] [48] . For this reason TTV has been of great interest to the hemophilia community. Azzi et al. [49] showed that TTV viral genome was present in firstgeneration recombinant factor VIII and IX concentrates. On the other hand, the second-generation factor VIII product Refacto and recombinant factor IX (Benefix) did not contain TTV. Recently, the most common factor IX products, Mononine and Benefix, used to treat hemophilia B were shown not to contain TTV [50] . In 1996, two groups independently discovered a novel RNA virus and called it GB virus C (GBV-C) and hepatitis G virus (HGV), respectively [51, 52] . From this point on HGV will be used to refer to GBV-C. HGV is a member of the Flaviviridae family and its genome is similar to that of HCV. HGV has been found in FVIII concentrates and has been associated with acute and persistent hepatitis in humans. The long-term clinical significance of such an infection remains uncertain. In general, human HGV infection appears to be mild or clinically silent [31] . There have, however, been a few cases of fulminate hepatitis associated with HGV infection reported [51] . In addition, a recent study questions the cause or effect relationship between HGV and HIV progression. The detection of HGV RNA in blood products and in plasmaderived products further raises questions regarding blood safety [53] . Additionally, HGV's prevalence is well established. For instance, 1.72% of US blood donors are infected with this virus [54] , whereas in Japan the prevalence is 0.9% [55] . In hemophilia patients the prevalence rate rises to 18% [54] . If blood products are not treated with specific virucidal methods, it is likely that HGV will be present in factor concentrates. Among the other potential transfusion threats is the reemerging agent, West Nile Virus (WNV) [31] . It is considered re-emerging because of the cycle of outbreak and dormancy. In 1999, an outbreak of WNV in New York City deeply worried the scientific community in regards to contaminated blood supply used for transfusions. In 2000, WNV went dormant in the USA; only to re-appear in 2001. The infection quickly spread. In 2002, 4 patients received organ donations from the same person. All 4 developed WNV infection. The incident sparked the need to test the blood supply for WNV. That year, a minimum of 21 cases of transfusion-borne WNV infections were identified. The American Red Cross confirmed that 0.01% of blood donations tested positive for WNV (415 of 4.1 million donors). In some states the rate of infection is much higher, as in Kansas where it was 1:243 [31] . Nucleic acid testing (NAT) for WNV was licensed by the FDA in 2000. Importantly, virus inactivation steps commonly used during the manufacture of plasma derivatives, such as pasteurization for human albumin, solvent/detergent treatment for IVIG and FVIII, and vapor heating for FVIII inhibitor-bypassing activity, readily inactivate WNV essentially eliminating this virus from the source plasma [56] . Although the number of WNV infections continues to decrease each summer, epidemiological surveillance and donor screening will have to continue, as vector population carrying the WNV have increasingly adapted, allowing the virus to breed in any volume of liquid. The ability of WNV and other agents to adapt or mutate, especially with new capabilities to infect humans, remains a concern [57] . Another potential threat is the SEN virus (SENV), a distant cousin of TTV. Five SENV strains (A, B, H [formerly C], D, E) have been identified, from which SENV-H and SENV-D strains have been found in the highest proportion in cases with non-A to E hepatitis [58, 59] . Umemura and coworkers showed the presence of SENV DNA (strains D or H) in 86/286 patients who received blood transfusions during surgery [59] . This rate is 10 times higher than in cases where no transfusions were performed. Moreover, it was observed during post-transfusion follow-up, that newly acquired SENV infections were present in 92% of patients with non-A to E hepatitis and only 24% of patients who did not develop post-transfusion hepatitis; hence suggesting a link between non-A to E hepatitis and SENV [59] . Additionally, SENV infection was observed in 41% of patients who developed HCV. This rate is significantly lower than that of non-A to E hepatitis (92%) [58] . In recent years, there has been a growing concern in regards to variant Creutzfeldt-Jakob disease (vCJD) and the risks associated with its transmission [60] . In 1996, a new human form of CJD was identified in the UK [61] . At the time, infected patients had eaten meat during the severe outbreak of Bovine Spongiform Encephalopathy (BSE). Further studies linked the occurrence of vCJD to crossspecies transmission [62, 63] . In 2000, studies in mice [64] and sheep [65] showed the transmission of vCJD through blood transfusions, making vCJD a possible blood borne agent [66] . Epidemiological studies up to 2002 in humans had shown that transmission through the blood supply had not yet occurred [37, 67] . Unfortunately, two subsequent studies have provided evidence for the transfusion transmission of vCJD in humans [63, 68, 69] . Moreover, in 2003, UK announced death of a man who had received a blood transfusion from an infected individual [70] . It is believed that, to date, as many as 150 people in the UK may be infected as a result of blood transfusions [68] . At this time, no reliable test has been developed to determine vCJD contamination of blood or blood components [71] or for the diagnosis of infection in humans. The risk of transmission of CJD via clotting factor concentrates manufactured from plasma appears to be relatively low. Exclusion of potentially infected donors based on travel history and low prevalence of vCJD in the donor population are key factors. As more information is learned about the disease, it is advisable for health officials to take a proactive and aggressive approach toward minimizing risk. Rigorous decontamination protocols may be used on surgical instruments that have been exposed to tissue possibly contaminated with CJD [72] ; however, these harsh measures are not likely to be useful with blood and blood components including plasma. Manufacturing steps, with the potential for the removal of TSE agents, are under evaluation [73] Several safety measures are in place to prevent transmission of vCJD through the blood supply [14, 23, 67] . Presently, the only risk factor that can be associated with vCJD is the country of residence [74] . Regulatory agencies in several countries, including the FDA in the USA have policies in place to defer blood donors depending on their travel histories to endemic areas such as the UK. Although TSE agents (abnormal prion proteins) are known to be resistant to common inactivation techniques [75] , animal studies have shown that processes used for protein purification, such as those used to make factor concentrates, can contribute to remove abnormal prion proteins and reducing or eliminating infectivity [76, 77] . Similar results have been observed for human TSE strains, vCJD for instance [77] . Therefore the transmission risk of vCJD and other human TSE strains through concentrate products at disease-causing levels appears to be minimal [37, 74] . Despite this apparently low risk of infection, experts have therefore recommended that only therapies with the lowest level of risk should be used for care of patients with hemophilia [78] . Severe Acute Respiratory Syndrome corona virus (SARS-CoV) is a lipid-enveloped single stranded RNA virus. The SARS outbreak came into the media limelight in February 2003, after Chinese officials reported 305 cases to the World Health Organization. After 6 months the outbreak was contained but involved 8,000 cases in 29 countries including 800 deaths. During the outbreak, no known person-to-person blood transmission occurred [79, 80] . The incubation period for SARS is 4-6 days [80] , and most patients become ill within 2-10 days of exposure. The risk of blood transmission of SARS-CoV is a concern. The American Red Cross and others have in place a screening process to defer donors based on travel history, or recent health conditions, such as dry cough, or shortness of breath. Moreover, the donated blood undergoes several tests and inactivation procedures for HIV, HBV, HCV, and SARS, among other pathogens, which aim to ensure the safety of the nations' blood supply since the viral inactivation procedures are highly successful in elimination of lipid-enveloped single-stranded RNA viruses. Among other emerging threats is the Avian influenza virus (AFV) that causes Avian flu (Bird flu). The AFV is genetically different from the influenza virus that affects humans. AVF commonly infects birds, which is the natural host. Although, it is rare for AFV to infect humans, several outbreaks have been reported since 1997 [81] . None of these cases are known to have been transmitted through a The comparison refers to the differential evaluation of plasma-derived and recombinant anti-factor VIII products. The favored product is indicated after considering the risks, benefits, cost and alternatives of plasma-derived and recombinant anti-factor VIII products for each characteristic. human-to-human transmission route although this has been suggested indicating that the AFV may be mutating [82] . It should be noted that to date, most of the reported cases seem to have arisen from human contact with infected poultry [81] . Unfortunately, influenza viruses mutate often and can easily spread from birds to people and create an epidemic. Hence, it is crucial to aggressively monitor for new infections and any possible human-human transmissions. The presence of an inhibitor represents one of the most important complications of exposure to factor concentrate in hemophilia [83] . Anti-FVIII allo-antibodies develop in 20%-30% of individuals with congenital hemophilia A who are treated for bleeding with factor VIII concentrates. The rate of inhibitor formation in patients with severe hemophilia A treated with the first generation recombinant products Kogenate (Bayer) [5, [84] [85] [86] or Recombinate (Baxter) [25, [87] [88] [89] is similar to that observed in patients treated with plasma-derived products [90] . Therefore, these data lead to speculation that the purer recombinant product is not necessarily a safer product from an inhibitor standpoint. Similarly, the incidence of allergic reactions although relatively rare, remains a potential problem with high-purity products [6, 91] . The decision of which factor concentrate to use is one that generates considerable debate among patients, their parents and the physicians and nurses who care for these patients. The advantages of recombinant factor concentrates include theoretical improvements in microbiological safety. However, this improvement is not without increased cost of therapy. There is no evidence to suspect that recombinant products are more prone to induce the development of neutralizing antibodies against factor VIII or to be associated with allergic or other adverse events. For newly diagnosed and infection-naive patients, similar to those described in cases 2 and 3 respectively, recombinant factor concentrates offer the benefits of reduced microbiological exposures. With respect to the different recombinant products, those formulated without animal or human proteins should be preferred as the microbiological risk, however small or theoretical, is likely to be further reduced, virtually eliminating the possibility of blood-borne infectious disease. At times in the past, shortages of factor concentrates due to manufacturing regulatory issues have led to ''rationing'' of products. If in the future, recombinant products are again scarce, the youngest and previously un-exposed should preferentially receive priority for any available product. The patient who has existing infection, including HIV, HBV, or HCV, should consider the same issues when deciding on a factor concentrate as there may be interacting effects of co-infection or the introduction of a novel agent upon the progression of existing infectious disease. For example, the diminished hepatocellular disease in HIVinfected individuals co-infected with HCV when compared to those with HCV alone is due to the lack of an immune response against the HCV [53] . Unfortunately, co-infection with another agent, including emerging infections is likely to result in a less favorable clinical course, increasing the virulence of the pre-existing infection. The patient described in case 1 is such an individual who already is infected with HIV and HCV. The introduction of another infection may result in progression of one or both of the pre-existing infections. Therefore, irrespective of the infectious disease status of the patient with hemophilia, all should be afforded the opportunity to receive the safest factor concentrate, a recombinant product formulated without the addition of animal or human proteins and at a reasonable cost. Table IV summarizes the quintessential issues in choosing between a plasma-derived, monoclonal antibody purified factor concentrate and a recombinant factor VIII product. In Table V , the products available in the USA to treat hemophilia are reviewed. All are treated to inactive viruses, demonstrate similar clinical efficacy to treat and prevent bleeding as well as show no difference in the induction of inhibitors. The single distinguishing feature is the possibility of exposure to an unanticipated infectious agent that causes human disease. It is this difference, whether real or potential, that currently plays most heavily in the decision making process of physicians who prescribe anti-hemophilic factor concentrates and the patients and parents who use these life-saving drugs. MASAC recommendations concerning the treatment of hemophilia and other bleeding disorders. National Hemophilia Foundation Clinical Practice Guidelines. Hemophilia and von Willebrand's Disease (2. Management; Update 2): Association of Hemophlia Clinic Directors of Canada The use of purified clotting factor concentrates in hemophilia. Influence of viral safety, cost, and supply on therapy World Federation of Hemophilia Safety and efficacy of KOGENATE Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs) Treatment of hemophilia: Recombinant factors only? Yes Treatment of hemophilia: Recombinant factors only? No Safety of therapeutic products used for hemophilia patients Leads from the MMWR. Safety of therapeutic products used for hemophilia patients Human recombinant factor IX: Safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates Treatment strategies in children with hemophilia Hepatitis B virus infection-natural history and clinical consequences Incidence of infection with hepatitis B virus in 56 patients with haemophilia A 1971-1979 Blood safety monitoring among persons with bleeding disorders-United States Advances in chronic viral hepatitis The incidence of viremia and the heterogeneity of hepatitis C virus genotypes among blood donors, hemophiliacs and patients with chronic liver disease AIDS-the first 20 years The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy-International Kogenate-FS Study Group The spectrum of safety: A review of the safety of current hemophilia products Safety issues affecting hemophilia products From the Centers for Disease Control and Prevention. Blood safety monitoring among persons with bleeding disorders-United States A multicenter pharmacosurveillance study for the evaluation of the efficacy and safety of recombinant factor VIII in the treatment of patients with hemophilia A. German Kogenate Study Group A multicenter study of recombinant factor VIII (recombinate): Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group Bdomain deleted factor VIII (r-VIII SQ): pharmacokinetics and initial safety aspects in hemophilia A patients Human recombinant DNAderived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: Final report on a hallmark clinical investigation Effect of using safer blood products on prevalence of HIV infection in haemophilic Canadians. Canadian Hemophilia Clinic Directors Group CDC/hemophilia study targets blood safety and joint disease Clinical perspectives of emerging pathogens in bleeding disorders Emerging, re-emerging and submerging infectious threats to the blood supply Vaccination against hepatitis Avirus in French hemophilic children Hepatitis B vaccination in children with thalassemia, hemophilia and cancer Accelerated schedule of hepatitis B vaccination in patients with hemophilia Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3 Current status of viral safety of virus inactivated factor VIII and IX concentrates in treatment of hemophilia Emerging risks of treatment The World Federation of Hemophilia's third global forum on the safety and supply of hemophilia treatment products Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1 T-helper cell-mediated interferon-gamma, interleukin-10 and proliferation responses to a candidate recombinant vaccine for human parvovirus B19 A nonproliferating parvovirus vaccine vector elicits sustained, protective humoral immunity following a single intravenous or intranasal inoculation Successful treatment with cyclosporine and high-dose gamma immunoglobulin for persistent parvovirus B19 infection in a patient with refractory autoimmune hemolytic anemia Human parvovirus B19 Contamination of coagulation factor concentrates with human parvovirus B19 genotype 1 and 2 Human parvovirus B19 in young male patients with hemophilia A: Associations with treatment product exposure and joint range-of-motion limitation A novel DNA virus (TTV) associated with elevated transaminase levels in posttransfusion hepatitis of unknown etiology Molecular and biophysical characterization of TT virus: Evidence for a new virus Pediatr Blood Cancer DOI 10.1002/pbc family infecting humans Circular double-stranded forms of TT virus DNA in the liver TT virus contaminates firstgeneration recombinant factor VIII concentrates Transfusion-transmitted virus is not present in factor IX concentrates commonly used to treat haemophilia B Molecular cloning and disease association of hepatitis G virus: A transfusion-transmissible agent Identification of two flavivirus-like genomes in the GB hepatitis agent Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Multicenter Hemophilia Cohort Study GB virus C/Hepatitis G virus infection is frequent in American children and young adults GB virus-C/hepatitis G virus West Nile virus and the safety of plasma derivatives: Verification of high safety margins, and the validity of predictions based on model virus data Emerging viral diseases and infectious disease risks Insights into SEN virus prevalence, transmission, and treatment in community-based persons and patients with liver disease referred to a liver disease unit SEN virus infection and its relationship to transfusion-associated hepatitis The public health impact of prion diseases A new variant of Creutzfeldt-Jakob disease in the UK Prion disease: Horizontal prion transmission in mule deer Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy Transmission of BSE by blood transfusion in sheep Variant CJD transmission through blood: Risks to predictors and ''predictees Blood infectivity in transmissible spongiform encephalopathies Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion Variant Creutzfeldt-Jakob disease: Risk of transmission by blood and blood products Deaths from variant Creutzfeldt-Jakob disease in the UK Impacts and concerns for vCJD in blood transfusion: Current status Effects on instruments of the World Health Organization-recommended protocols for decontamination after possible exposure to transmissible spongiform encephalopathy-contaminated tissue Transmissible Spongiform Encephalopathies. Managing risk in mammalian organs, cells and sera Surveillance for Creutzfeldt-Jakob disease among persons with hemophilia Inactivation of prions by physical and chemical means A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma Clinical implications of emerging pathogens in haemophilia: The variant Creutzfeldt-Jakob disease experience Cumulative number of reported cases of severe acute respiratory syndrome (SARS) Update: Severe acute respiratory syndrome-United States Update: Influenza Activity-United States and Worldwide, 2002-03 Season, and Composition of the 2003-04 Influenza Vaccine Inhibitors in congenital coagulation disorders Clinical trials of the recombinant factor VIII product, Kogenate Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group Clinical evaluation of a recombinant factor VIII preparation (Kogenate) in previously untreated patients with hemophilia A Current status of clinical studies of recombinant factor VIII (recombinate) in patients with hemophilia A. Recombinate Study Group Recombinate study Summary of clinical experience with recombinant factor VIII products-recombinate Inhibitor development in previously untreated patients with hemophilia A: A prospective long-term follow-up comparing plasma-derived and recombinant products Blood products for hemophilia: Past, present and future The authors thank Keith Hoots, Emily Czapek and Margaret Telfer for their critical review of the manuscript and thoughtful comments and suggestions. This work is dedicated to the patients and families who have suffered as a result of complications due to the treatment of hemophilia and, in particular, factor concentrates tainted with bloodborne infectious agents.